Throughout this application, various references are identified by authors and full citations. Disclosures of these publications in their entireties are hereby incorporated by reference into this application to more fully describe the state of the art to which this invention pertains.
Bipolar mood disorder commonly begins with depression and is characterized by at least one elated period sometime during the course of the illness. In bipolar I disorder, full blown manic and major depressive episodes alternate. In bipolar II disorder, depressive episodes alternate with hypomanias (i.e., mild, nonpsychotic periods of excitement) of relatively short duration. Although insomnia and poor appetite do occur during the depressive phase of bipolar illness, such atypical depressive signs as hypersomnia and overeating are more characteristic and may recur on a seasonal basis (e.g., in the autumn or winter).
In full blown manic psychosis, the mood typically is one of elation, but irritability and frank hostility are not uncommon. The patient""s lack of insight and inordinate capacity for activity lead to a dangerously explosive psychotic state, in which the individual is impatient, intrusive, and meddlesome and responds with aggressive irritability when crossed. Interpersonal friction results and may lead to secondary paranoid delusional interpretations of being persecuted. Audio and visual hallucinations are sometime present, occur at the high mania, and are usually understandably linked with the morbid mood. The need for sleep is decreased. Manic persons are inexhaustibly, excessively, and impulsively involved in various activities without recognizing the inherent social dangers.
Mixed states are labile mixtures between depressive and manic manifestations or rapid alternation from one state to the other and commonly occur in manic depressive at one time or another. (The Merck Manual 16th edition, 1992, p. 1592, 1593, 1599) Bipolar disorder (BP) affects 1-2% of the population.
The classical psychopharmaceuticals effective in the treatment of mood disorders can be grouped into three classes: the heterocyclic anti depressants (HCA), monoamine oxidase inhibitors (MAOI) and lithium salts. (Merck, p. 1603). While HCA and MAOI drugs are indicated for the depressive phase of the bipolar disorder, lithium is known to attenuate the bipolar mood swings.
Only around 70% of the patients are considered to respond to the treatment with HCA or lithium drugs (Merck, p. 1604, 1607). For the resistant and refractory disease, combinations of drugs are used, increasing even more the panel o f characteristic side effects.
In light of this situation, there is a continuous search for new drugs aimed to solve the problems of drug resistance and severe side effects. Lately, drugs like valproic acid, carbamazepin, verapamil, propanolol, clonidine and adenyl cyclase inhibitors have been found to be beneficial either alone or as adjunct therapy for manic patients. (O. Kaufman and R. H. Belmaker, P. Soubrie, ed.: Anxiety, Depression and Mania. Anim. Models Psychiatr. Disord., Basel, Karger, 1991, 3, pp. 103-121).
In order to discover new drugs, rodent models relevant to the manic phase, like amphetamine, amphetamine with chlordiazepoxide, morphine or desmethylimipramine induced hyperactivity or to the depression phase like immobilizations, are usually used (D. L. Murphy, Anim. Mod. Psych. Neur., 1977, pp. 211-225).
These mania models focus on an induced increase in the activity level of the animal (e.g., locomotor or/and vertical activity) as a parallel to the hyperactivity of the maniac patient. The reversal of the induced hyperactivity in rodents by their pretreatment with a drug of interest indicates the possible efficacy of this drug in the treatment of human mania.
A variety of substituted 1-aminoindans have been proposed to have some activity in the central nervous system (CNS). This group of compounds has a wide range of activities, for example, U.S. Pat. No. 4,096,173 discloses 1-aminoindans with ring chloro substituents as having anti-allergic, anti-spasmodic and local anesthetic activities, whereas U.S Pat. No. 3,886,168 discloses the anti-inflammatory and vasodilatory activity of certain 1-aminoindans.
It is hypothesized therein that the activity may be based in the CNS though no evidence is provided or suggested to support the hypothesis. British Patent No. 852,735 discloses 1-aminoindans with a lower alkoxy group in the five position as being active in dilating coronary blood vessels.
U.S. Pat. No. 3,637,740 discloses dl-1-N,N-dimethylamino-4-methoxy-7-chloroindane as an antidepressant and/or an antianxiety agent. However, no clear evidence is provided of either activity.
Horne et al. (J. Pharm. Exp. Ther. 1972, 180(3), p. 523) have shown that 2-aminoindan is a far superior inhibitor of catecholamine uptake than 1-aminoindan and therefore dismissed the latter as a candidate for use in the treatment of Parkinson""s Disease. Martin et al. (J. Med. Chem. 1973, 16(2), p. 147; J. Med. Chem. 1974, 17(4), p. 409) describe experiments wherein N-methyl-5-methoxy derivatives of 1-aminoindan are investigated as having monoamine oxidase (MAO) inhibitory activity.
Oshiro et al. (J. Med. Chem. 1991, 34, pp. 2004-2013) disclose a wide range of 7-hydroxy-1-aminoindan derivatives that they subjected to screening for use as cerebroprotective agents using an antihypoxic test and as CNS stimulatory agents using a cerebral trauma test. In the resultant structure-activity-analysis, it was found that replacement of the 7-hydroxy group by a methoxy group resulted in loss of activity in the antihypoxic test but not in the cerebral trauma test. Their conclusion was that the 7-hydroxy is essential to obtain the desired activity. This is evident from their subsequent paper wherein a broader range of 7-hydroxy derivatives are screened (J. Med. Chem. 1991, 34, 2014-2020). These 7-hydroxy-1-aminoindans are defined in U.S. Pat. Nos. 4,788,130; 4,792,628; 4,895,847; 5,055,474; and 5,242,919, all assigned to Otsuka Pharmaceutical Co., Japan.
Cohen et al. describe the use of a series of aminoindans for the treatment of Parkinson""s disease, dementia, epilepsy, convulsions or seizures and neurotrauma and disclose the preparation of certain novel representatives of that class. (U.S. Pat. Nos. 5,877,221; 5,880,159; 5,877,218).
The subject invention describes a method of treating mania in the bipolar mood disorder in a subject comprising administering to the subject a therapeutically effective amount of derivatives of 1-aminoindan, their racemic mixtures, enantiomers, and salts thereof, of the general formula: 
wherein n is 0 or 1;
each of R1 and R2 are hydrogen, C1-C4 alkyl, halogen;
R3 is hydrogen, C1-C4 alkyl, hydroxy, C1-C4 alkoxy;
R4 is hydrogen, C1-C4 alkyl;
R6 is hydrogen, substituted or unsubstituted C1-C12 alkyl, C6-C12 aryl, C7-C12 aralkyl or Axe2x80x94Nxe2x80x94R9R10, provided that R6 is not methyl when R1, R2, R3 and R4 are hydrogen atoms,
wherein A is substituted or unsubstituted C1-C12 alkyl, substituted or unsubstituted C6-C12 aryl, substituted or unsubstituted C7-C12 aralkyl, and each of R9 and R10 are independently hydrogen, C1-C12 alkyl, C6-C12 aryl, C7-C12 aralkyl, COOtBu, or indanyl;
and racemic mixtures, enantiomers, and salts thereof.